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8bcr
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8bcr]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Dengue_virus_3 Dengue virus 3]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8BCR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8BCR FirstGlance]. <br> | <table><tr><td colspan='2'>[[8bcr]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Dengue_virus_3 Dengue virus 3]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8BCR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8BCR FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AT9:[[(2R,3R,4R,5R)-5-(2-azanyl-6-oxidanylidene-1H-purin-9-yl)-4-fluoranyl-4-methyl-3-oxidanyl-oxolan-2-yl]methoxy-oxidanyl-phosphoryl]+phosphono+hydrogen+phosphate'>AT9</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AT9:[[(2R,3R,4R,5R)-5-(2-azanyl-6-oxidanylidene-1H-purin-9-yl)-4-fluoranyl-4-methyl-3-oxidanyl-oxolan-2-yl]methoxy-oxidanyl-phosphoryl]+phosphono+hydrogen+phosphate'>AT9</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8bcr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8bcr OCA], [https://pdbe.org/8bcr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8bcr RCSB], [https://www.ebi.ac.uk/pdbsum/8bcr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8bcr ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8bcr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8bcr OCA], [https://pdbe.org/8bcr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8bcr RCSB], [https://www.ebi.ac.uk/pdbsum/8bcr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8bcr ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/A9LIE0_9FLAV A9LIE0_9FLAV] Envelope protein E binding to host cell surface receptor is followed by virus internalization through clathrin-mediated endocytosis. Envelope protein E is subsequently involved in membrane fusion between virion and host late endosomes. Synthesized as a homodimer with prM which acts as a chaperone for envelope protein E. After cleavage of prM, envelope protein E dissociate from small envelope protein M and homodimerizes (By similarity).[SAAS:SAAS013754_004_099774] | [https://www.uniprot.org/uniprot/A9LIE0_9FLAV A9LIE0_9FLAV] Envelope protein E binding to host cell surface receptor is followed by virus internalization through clathrin-mediated endocytosis. Envelope protein E is subsequently involved in membrane fusion between virion and host late endosomes. Synthesized as a homodimer with prM which acts as a chaperone for envelope protein E. After cleavage of prM, envelope protein E dissociate from small envelope protein M and homodimerizes (By similarity).[SAAS:SAAS013754_004_099774] | ||
| - | <div style="background-color:#fffaf0;"> | ||
| - | == Publication Abstract from PubMed == | ||
| - | AT-752 is a guanosine analogue prodrug active against dengue virus (DENV). In infected cells, it is metabolized into 2'-methyl-2'-fluoro guanosine 5'-triphosphate (AT-9010) which inhibits RNA synthesis in acting as a RNA chain terminator. Here we show that AT-9010 has several modes of action on DENV full-length NS5. AT-9010 does not inhibit the primer pppApG synthesis step significantly. However, AT-9010 targets two NS5-associated enzyme activities, the RNA 2'-O-MTase and the RNA-dependent RNA polymerase (RdRp) at its RNA elongation step. Crystal structure and RNA methyltransferase (MTase) activities of the DENV 2 MTase domain in complex with AT-9010 at 1.97 A resolution shows the latter bound to the GTP/RNA-cap binding site, accounting for the observed inhibition of 2'-O but not N7-methylation activity. AT-9010 is discriminated approximately 10 to 14-fold against GTP at the NS5 active site of all four DENV1-4 NS5 RdRps, arguing for significant inhibition through viral RNA synthesis termination. In Huh-7 cells, DENV1-4 are equally sensitive to AT-281, the free base of AT-752 (EC(50) approximately 0.50 muM), suggesting broad spectrum antiviral properties of AT-752 against flaviviruses. | ||
| - | |||
| - | AT-752 targets multiple sites and activities on the Dengue virus replication enzyme NS5.,Feracci M, Eydoux C, Fattorini V, Lo Bello L, Gauffre P, Selisko B, Sutto-Ortiz P, Shannon A, Xia H, Shi PY, Noel M, Debart F, Vasseur JJ, Good S, Lin K, Moussa A, Sommadossi JP, Chazot A, Alvarez K, Guillemot JC, Decroly E, Ferron F, Canard B Antiviral Res. 2023 Mar 9;212:105574. doi: 10.1016/j.antiviral.2023.105574. PMID:36905944<ref>PMID:36905944</ref> | ||
| - | |||
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 8bcr" style="background-color:#fffaf0;"></div> | ||
| - | == References == | ||
| - | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Revision as of 08:17, 7 February 2024
DENV3 Methyltransferase in complexed with AT-9010 and SAH
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